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61.
Chunbin Zou Yan Chen Rebecca M. Smith Courtney Snavely Jin Li Tiffany A. Coon Bill B. Chen Yutong Zhao Rama K. Mallampalli 《The Journal of biological chemistry》2013,288(9):6306-6316
Histone acetyltransferase binding to origin recognition complex (HBO1) plays a crucial role in DNA replication licensing and cell proliferation, yet its molecular regulation in cells is relatively unknown. Here an uncharacterized protein, Fbxw15, directly interacts with HBO1, a labile protein (t½ = ∼3 h), to mediate its ubiquitination (Lys338) and degradation in the cytoplasm. Fbxw15-mediated HBO1 depletion required mitogen-activated protein kinase 1 (Mek1), which was sufficient to trigger HBO1 phosphorylation and degradation in cells. Mek1 ability to produce HBO1 degradation was blocked by Fbxw15 silencing. Lipopolysaccharide induced HBO1 degradation, an effect abrogated by Fbxw15 or Mek1 cellular depletion. Modulation of Fbxw15 levels was able to differentially regulate histone H3K14 acetylation and cellular proliferation by altering HBO1 levels. These studies authenticate Fbxw15 as a ubiquitin E3 ligase subunit that mediates endotoxin-induced HBO1 depletion in cells, thereby controlling cell replicative capacity. 相似文献
62.
Courtney M. Tate Wayne Blosser Lisa Wyss Glenn Evans Qi Xue Yong Pan Louis Stancato 《The Journal of biological chemistry》2013,288(9):6743-6753
LY2228820 dimesylate is a highly selective small molecule inhibitor of p38α and p38β mitogen-activated protein kinases (MAPKs) that is currently under clinical investigation for human malignancies. p38 MAPK is implicated in a wide range of biological processes, in particular those that support tumorigenesis. One such process, angiogenesis, is required for tumor growth and metastasis, and many new cancer therapies are therefore directed against the tumor vasculature. Using an in vitro co-culture endothelial cord formation assay, a surrogate of angiogenesis, we investigated the role of p38 MAPK in growth factor- and tumor-driven angiogenesis using LY2228820 dimesylate treatment and by shRNA gene knockdown. p38 MAPK was activated in endothelial cells upon growth factor stimulation, with inhibition by LY2228820 dimesylate treatment causing a significant decrease in VEGF-, bFGF-, EGF-, and IL-6-induced endothelial cord formation and an even more dramatic decrease in tumor-driven cord formation. In addition to involvement in downstream cytokine signaling, p38 MAPK was important for VEGF, bFGF, EGF, IL-6, and other proangiogenic cytokine secretion in stromal and tumor cells. LY2228820 dimesylate results were substantiated using p38α MAPK-specific shRNA and shRNA against the downstream p38 MAPK effectors MAPKAPK-2 and HSP27. Using in vivo models of functional neoangiogenesis, LY2228820 dimesylate treatment reduced hemoglobin content in a plug assay and decreased VEGF-A-stimulated vascularization in a mouse ear model. Thus, p38α MAPK is implicated in tumor angiogenesis through direct tumoral effects and through reduction of proangiogenic cytokine secretion via the microenvironment. 相似文献
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Shahana Safdar Courtney A. Payne Nam H. Tu Lakeshia J. Taite 《Biotechnology and bioengineering》2013,110(4):1211-1220
Glioblastoma multiforme is the most common malignant central nervous system tumor, and also among the most difficult to treat due to a lack of response to chemotherapeutics. New methods of countering the mechanisms that confer chemoresistance to malignant gliomas could lead to significant advances in the quest to identify novel drug combinations or targeted drug delivery systems for cancer therapy. In this study, we investigate the use of a targeted nitric oxide (NO) donor as a pretreatment to sensitize glioma cells to chemotherapy. The protein chlorotoxin (CTX) has been shown to preferentially target glioma cells, and we have developed CTX–NO, a glioma‐specific, NO‐donating CTX derivative. Pretreatment of cells with CTX–NO followed by 48‐h exposure to either carmustine (BCNU) or temozolomide (TMZ), both common chemotherapeutics used in glioma treatment, resulted in increased efficacy of both therapeutics. After CTX–NO exposure, both T98G and U‐87MG human malignant glioma cells show increased sensitivity to BCNU and TMZ. Further investigation revealed that the consequences of this combination therapy was a reduction in active levels of the cytoprotective enzyme MGMT and altered p53 activity, both of which are essential in DNA repair and tumor cell resistance to chemotherapy. The combination of CTX–NO and chemotherapeutics also led to decreased cell invasion. These studies indicate that this targeted NO donor could be an invaluable tool in the development of novel approaches to treat cancer. Biotechnol. Bioeng. 2013; 110: 1211–1220. © 2012 Wiley Periodicals, Inc. 相似文献
64.
Martin Plath Markus Pfenninger Hannes Lerp Rüdiger Riesch Christoph Eschenbrenner Patrick A. Slattery David Bierbach Nina Herrmann Matthias Schulte Lenin Arias–Rodriguez Jeane Rimber Indy Courtney Passow Michael Tobler 《Evolution; international journal of organic evolution》2013,67(9):2647-2661
We investigated mechanisms of reproductive isolation in livebearing fishes (genus Poecilia) inhabiting sulfidic and nonsulfidic habitats in three replicate river drainages. Although sulfide spring fish convergently evolved divergent phenotypes, it was unclear if mechanisms of reproductive isolation also evolved convergently. Using microsatellites, we found strongly reduced gene flow between adjacent populations from different habitat types, suggesting that local adaptation to sulfidic habitats repeatedly caused the emergence of reproductive isolation. Reciprocal translocation experiments indicate strong selection against immigrants into sulfidic waters, but also variation among drainages in the strength of selection against immigrants into nonsulfidic waters. Mate choice experiments revealed the evolution of assortative mating preferences in females from nonsulfidic but not from sulfidic habitats. The inferred strength of sexual selection against immigrants (RIs) was negatively correlated with the strength of natural selection (RIm), a pattern that could be attributed to reinforcement, whereby natural selection strengthens behavioral isolation due to reduced hybrid fitness. Overall, reproductive isolation and genetic differentiation appear to be replicated and direct consequences of local adaptation to sulfide spring environments, but the relative contributions of different mechanisms of reproductive isolation vary across these evolutionarily independent replicates, highlighting both convergent and nonconvergent evolutionary trajectories of populations in each drainage. 相似文献
65.
Beguiling and risky: ‘environmental works and measures’ for wetland conservation under a changing climate 总被引:1,自引:0,他引:1
In Australia’s Murray–Darling Basin, small-scale engineering works called ‘environmental works and measures’ have been implemented as a basis for river and other wetland conservation. While implementing these, governments seem to have embraced the beguiling notion that scarce water supplies can be divided further, while conserving the environment and maintaining agricultural production. The difficulties in doing this are expected to increase in the face of extreme climate variability. With this scenario as a backdrop, the $280 million (Monetary values ($) in this paper are in Australian dollars (AUD). At the time of writing AUD $1.00 = ~USD $1.02.) Living Murray and related programmes are assessed to see whether microengineering works to manage the hydrology of wetlands make for effective adaptation to water scarcity and climate change or whether it amounts to an overly narrow adaptation or maladaptation. Some measures were found to be substantially beneficial, such as the construction of fishways. However, under these programmes, only 0.6% of the Basin’s wetlands would be inundated and there are significant risks including desiccation of non-target wetlands and further reductions in water allocations for the environment. It is recommended that trade-offs between alternative strategies are assessed as the basis for minimising perverse impacts under changing climatic and hydrological conditions. 相似文献
66.
Zheng Zhang Sriram Jakkaraju Joy Blain Kenneth Gogol Lei Zhao Robert C. Hartley Courtney A. Karlsson Bart L. Staker Thomas E. Edwards Lance J. Stewart Peter J. Myler Michael Clare Darren W. Begley James R. Horn Timothy J. Hagen 《Bioorganic & medicinal chemistry letters》2013,23(24):6860-6863
Published biological data suggest that the methyl erythritol phosphate (MEP) pathway, a non-mevalonate isoprenoid biosynthetic pathway, is essential for certain bacteria and other infectious disease organisms. One highly conserved enzyme in the MEP pathway is 2C-methyl-d-erythritol 2,4-cyclodiphosphate synthase (IspF). Fragment-bound complexes of IspF from Burkholderia pseudomallei were used to design and synthesize a series of molecules linking the cytidine moiety to different zinc pocket fragment binders. Testing by surface plasmon resonance (SPR) found one molecule in the series to possess binding affinity equal to that of cytidine diphosphate, despite lacking any metal-coordinating phosphate groups. Close inspection of the SPR data suggest different binding stoichiometries between IspF and test compounds. Crystallographic analysis shows important variations between the binding mode of one synthesized compound and the pose of the bound fragment from which it was designed. The binding modes of these molecules add to our structural knowledge base for IspF and suggest future refinements in this compound series. 相似文献
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Jacques Amar Céline Lange Ga?lle Payros Celine Garret Chantal Chabo Olivier Lantieri Michael Courtney Michel Marre Marie Aline Charles Beverley Balkau Rémy Burcelin D.E.S.I.R. Study Group 《PloS one》2013,8(1)